Sen De Ning

Sen De Ning is indicated in combination with levodopa/benserazide or levodopa/carbidopa for use in patients with levodopa-responsive idiopathic Parkinson's disease and motor fluctuations, who failed to respond to or are intolerant of other catechol-O-methyl transferase COMT inhibitors. Because of the risk of potentially fatal, acute liver injury, Sen De Ning should not be considered as a first-line adjunct therapy to levodopa/benserazide or levodopa/carbidopa

Since Sen De Ning should be used only in combination with levodopa/benserazide and levodopa/carbidopa, the prescribing information for these levodopa preparations is also applicable to their concomitant use with Sen De Ning.

Posology

Paediatric population

Sen De Ning is not recommended for use in children below the age of 18 due to insufficient data on safety or efficacy. There is no relevant indication for use in children and adolescents.

Elderly patients

No dose adjustment of Sen De Ning is recommended for elderly patients.

Patients with hepatic impairment

Sen De Ning is contraindicated for patients with liver disease or increased liver enzymes.

Patients with renal impairment

No dose adjustment of Sen De Ning is recommended for patients with mild or moderate renal impairment (creatinine clearance of 30 ml/min or greater). Patients with severe renal impairment (creatinine clearance < 30 ml/min) should be treated with caution. No information on the tolerability of tolcapone in these populations is available

Method of administration

The administration of Sen De Ning is restricted to prescription and supervision by physicians experienced in the management of advanced Parkinson's disease.

Sen De Ning is administered orally three times daily.

Sen De Ning may be taken with or without food

Sen De Ning tablets are film-coated and should be swallowed whole because tolcapone has a bitter taste.

Sen De Ning can be combined with all pharmaceutical formulations of levodopa/benserazide and levodopa/carbidopa (see also section 4.5)

The first dose of the day of Sen De Ning should be taken together with the first dose of the day of a levodopa preparation, and the subsequent doses should be given approximately 6 and 12 hours later. Sen De Ning may be taken with or without food

The recommended dose of Sen De Ning is 100 mg three times daily, always as an adjunct to levodopa/benserazide or levodopa/carbidopa therapy. Only in exceptional circumstances, when the anticipated incremental clinical benefit justifies the increased risk of hepatic reactions, should the dose be increased to 200 mg three times daily. If substantial clinical benefits are not seen within 3 weeks of the initiation of the treatment (regardless of dose) Sen De Ning should be discontinued.

The maximum therapeutic dose of 200 mg three times daily should not be exceeded, as there is no evidence of additional efficacy at higher doses.

Liver function should be checked before starting treatment with Sen De Ning and then monitored every 2 weeks for the first year of therapy, every 4 weeks for the next 6 months and every 8 weeks thereafter. If the dose is increased to 200 mg tid, liver enzyme monitoring should take place before increasing the dose and then be reinitiated following the same sequence of frequencies as above

Sen De Ning treatment should also be discontinued if ALT (alanine amino transferase) and/or AST (aspartate amino transferase) exceed the upper limit of normal or symptoms or signs suggest the onset of hepatic failure

Levodopa adjustments during Sen De Ning treatment:

As Sen De Ning decreases the breakdown of levodopa in the body, side effects due to increased levodopa concentrations may occur when beginning Sen De Ning treatment. In clinical trials, more than 70 % of patients required a decrease in their daily levodopa dose if their daily dose of levodopa was >600 mg or if patients had moderate or severe dyskinesia before beginning treatment.

The average reduction in daily levodopa dose was about 30 % in those patients requiring a levodopa dose reduction. When beginning Sen De Ning, all patients should be informed of the symptoms of excessive levodopa dosage and what to do if it occurs.

Levodopa adjustments when Sen De Ning is discontinued:

The following suggestions are based on pharmacological considerations and have not been evaluated in clinical trials. Levodopa dose should not be decreased when Sen De Ning therapy is being discontinued due to side effects related to too much levodopa. However, when Sen De Ning therapy is being discontinued for reasons other than too much levodopa, the levodopa dose may have to be increased to levels equal to or greater than before initiation of Sen De Ning therapy, especially if the patient had large decreases in levodopa when starting Sen De Ning. In all cases, patients should be educated on the symptoms of levodopa under-dose and what to do if it occurs. Adjustments in levodopa are most likely to be required within 1-2 days of Sen De Ning discontinuation.

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- Evidence of liver disease or increased liver enzymes

- Severe dyskinesia

- A previous history of Neuroleptic Malignant Syndrome (NMS) Symptom Complex and /or non-traumatic Rhabdomyolysis or Hyperthermia

- Phaeochromocytoma

- Treatment with non-selective monoamino oxidase (MAO) inhibitors.

Impulse control disorders: Patients should be regularly monitored for the development of impulse control disorders.). Selective MAO-B inhibitors should not be used at higher than recommended doses (e.g. selegiline 10 mg/day) when co-administered with Sen De Ning.

Warfarin: Since clinical information is limited regarding the combination of warfarin and tolcapone, coagulation parameters should be monitored when these drugs are co-administered.

Special populations: Patients with severe renal impairment (creatinine clearance <30 ml/min) should be treated with caution. No information on the tolerability of tolcapone in these populations is available

Lactose intolerance: Sen De Ning contains lactose. Patients with hereditary problems of galactose intolerance, the Lapp lactose deficiency or glucose-galactose malabsorption should not take this medicine.

No studies on the effects of Sen De Ning on the ability to drive and use machines have been performed.

There is no evidence from clinical studies that Sen De Ning adversely influences a patient's ability to drive and use machines.)

The most commonly observed adverse reactions associated with the use of Sen De Ning, occurring more frequently than in placebo-treated patients are listed in the table below. However, Sen De Ning, as a COMT inhibitor, is known to increase the bioavailability of the co-adminstered levodopa. The consequent increase in dopaminergic stimulation can lead to the dopaminergic side effects observed after treatment with COMT inhibitors. The most common of these are increased dyskinesia, nausea, vomiting, abdominal pain, syncope, orthostatic complaints, constipation, sleep disorders, somnolence, hallucinations.

The only adverse reactions commonly leading to discontinuation of Sen De Ning in clinical trials was diarrhoea

Very common (>1/10)

Common (>1/100 to <1/10)

Uncommon (>1/1,000 to < 1/100)

Rare (>1/10,000 to <1/1,000)

Very rare (<1/10,000), not known (cannot be estimated from the available data)

Experience with Sen De Ning obtained in parallel placebo-controlled randomised studies in patients with Parkinson's disease is shown in the following table, which lists adverse reactions with a potential relationship to Sen De Ning.

Summary of potentially Sen De Ning-related adverse reactions, with crude incidence rates for the phase III placebo-controlled studies:

*Adverse reactions for which no frequency could be derived from clinical studies (i.e. where a specific adverse reaction was not observed in clinical trials but was reported post-marketing only) are indicated by an asterisk (*), and the frequency category has been calculated according to EU Guideline.

Increase of alanine aminotransferase

Increases to more than three times the upper limit of normal (ULN) in alanine aminotransferase (ALT) occurred in 1 % of patients receiving Sen De Ning 100 mg three times daily, and 3 % of patients at 200 mg three times daily. Increases were approximately two times more likely in females. The increases usually appeared within 6 to 12 weeks of starting treatment, and were not associated with any clinical signs or symptoms. In about half the cases, transaminase levels returned spontaneously to baseline values whilst patients continued Sen De Ning treatment. For the remainder, when treatment was discontinued, transaminase levels returned to pre-treatment levels.

Hepatocellular injury

Rare cases of severe hepatocellular injury resulting in death have been reported during marketed use

Neuroleptic Malignant Syndrome Symptom Complex

Isolated cases of patients with symptoms suggestive of Neuroleptic Malignant Syndrome Symptom Complex have been reported following reduction or discontinuation of Sen De Ning and following introduction of Sen De Ning when this was accompanied by a significant reduction in other concomitant dopaminergic medications.'Special Warnings and Precautions for use')

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

Isolated cases of either accidental or intentional overdose with tolcapone tablets have been reported. However clinical circumstances of these cases were so diverse, that no general conclusions can be drawn from the cases.

The highest dose of tolcapone administered to humans was 800 mg three times daily, with and without levodopa coadministration, in a one week study in healthy elderly volunteers. The peak plasma concentrations of tolcapone at this dose were on average 30 µg/ml (compared to 3 and 6 µg/ml with 100 mg tid and 200 mg tid of tolcapone respectively). Nausea, vomiting and dizziness were observed, particularly in combination with levodopa.

Management of overdose: Hospitalisation is advised. General supportive care is indicated. Based on the physicochemical properties of the compound, haemodialysis is unlikely to be of benefit.

Pharmaco-therapeutic group: Anti-Parkinson drugs, other dopaminergic agents, ATC code: NO4BX01.

Mechanism of action:

Tolcapone is an orally active, selective and reversible catechol-O-methyltransferase (COMT) inhibitor. Administered concomitantly with levodopa and an aromatic amino acid decarboxylase inhibitor (AADC-I), it leads to more stable plasma levels of levodopa by reducing metabolism of levodopa to 3-methoxy-4-hydroxy-L-phenylalanine (3-OMD).

High levels of plasma 3-OMD have been associated with poor response to levodopa in Parkinson's disease patients. Tolcapone markedly reduces the formation of 3-OMD.

Pharmacodynamic effects:

Studies in healthy volunteers have shown that tolcapone reversibly inhibits human erythrocyte COMT activity after oral administration. The inhibition is closely related to plasma tolcapone concentration. With 200 mg tolcapone, maximum inhibition of erythrocyte COMT activity is, on average, greater than 80 %. During dosing with Sen De Ning 200 mg three times daily, erythrocyte COMT inhibition at trough is 30 % to 45 %, with no development of tolerance.

Transient elevation above pretreatment levels of erythrocyte COMT activity was observed after withdrawal of tolcapone. However, a study in Parkinson's patients confirmed that after treatment discontinuation there was no significant change in levodopa pharmacokinetics or in patient response to levodopa compared to pretreatment levels.

When Sen De Ning is administered together with levodopa, it increases the relative bioavailability (AUC) of levodopa approximately two-fold. This is due to a decrease in clearance in L-dopa resulting in a prolongation of the terminal elimination half-life (t_1/2) of levodopa. In general, the average peak levodopa plasma concentration (C_max) and the time of its occurrence (t_max) were unaffected. The onset of effect occurs after the first administration. Studies in healthy volunteers and parkinsonian patients have confirmed that the maximum effect occurs with 100 - 200 mg tolcapone. Plasma levels of 3-OMD were markedly and dose-dependently decreased by tolcapone when given with levodopa/AADC-I (aromatic amino acid decarboxylase - inhibitor) (benserazide or carbidopa).

Tolcapone's effect on levodopa pharmacokinetics is similar with all pharmaceutical formulations of levodopa/benserazide and levodopa/carbidopa; it is independent of levodopa dose, levodopa/AADC-I (benserazide or carbidopa) ratio and the use of sustained-release formulations.

Clinical efficacy and safety:

Double blind placebo controlled clinical studies have shown a significant reduction of approximately 20 % to 30 % in OFF time and a similar increase in ON time, accompanied by reduced severity of symptoms in fluctuating patients receiving Sen De Ning. Investigator's global assessments of efficacy also showed significant improvement.

A double-blind trial compared Sen De Ning with entacapone in Parkinson's disease patients who had at least three hours of OFF time per day while receiving optimised levodopa therapy. The primary outcome was the proportion of patients with a 1 or more hour increase in ON time (see Table 1).

Table 1: Primary and Secondary Outcome of Double-blind Trial

In the therapeutic range, tolcapone pharmacokinetics are linear and independent of levodopa/AADC-I (benserazide or carbidopa) coadministration.

Absorption: Tolcapone is rapidly absorbed with a t_max of approximately 2 hours. The absolute bioavailability of an oral administration is around 65 %. Tolcapone does not accumulate with three times daily dosing of 100 or 200 mg. At these doses, C_max is approximately 3 and 6 µg/ml, respectively. Food delays and decreases the absorption of tolcapone, but the relative bioavailability of a dose of tolcapone taken with a meal is still 80 % to 90 %.

Distribution: The volume of distribution (V_ss) of tolcapone is small (9 l). Tolcapone does not distribute widely into tissues due to its high plasma protein binding (>99.9 %). In vitro experiments have shown that tolcapone binds mainly to serum albumin.

Biotransformation/Elimination: Tolcapone is almost completely metabolised prior to excretion, with only a very small amount (0.5 % of dose) found unchanged in urine. The main metabolic pathway of tolcapone is conjugation to its inactive glucuronide. In addition, the compound is methylated by COMT to 3-O-methyl-tolcapone and metabolised by cytochromes P450 3A4 and P450 2A6 to a primary alcohol (hydroxylation of the methyl group), which is subsequently oxidised to the carboxylic acid. The reduction to a putative amine, as well as the subsequent N-acetylation, occurs to a minor extent. After oral administration, 60 % of drug-related material is excreted into urine and 40 % into faeces.

Tolcapone is a low-extraction-ratio drug (extraction-ratio = 0.15), with a moderate systemic clearance of about 7 L/h. The t_1/2 of tolcapone is approximately 2 hours.

Hepatic impairment: Because of the risk of liver injury observed during post-marketing use, Sen De Ning is contraindicated in patients with liver disease or increased liver enzymes. A study in patients with hepatic impairment has shown that moderate non-cirrhotic liver disease had no impact on the pharmacokinetics of tolcapone. However, in patients with moderate cirrhotic liver disease, clearance of unbound tolcapone was reduced by almost 50 %. This reduction may increase the average concentration of unbound drug two-fold.

Renal impairment: The pharmacokinetics of tolcapone has not been investigated in patients with renal impairment. However, the relationship of renal function and tolcapone pharmacokinetics has been investigated using population pharmacokinetics during clinical trials. The data of more than 400 patients have confirmed that over a wide range of creatinine clearance values (30-130 mL/min) the pharmacokinetics of tolcapone are unaffected by renal function. This could be explained by the fact that only a negligible amount of unchanged tolcapone is excreted in the urine, and the main metabolite, tolcapone-glucuronide, is excreted both in urine and in bile (faeces).

• R52.1 – Chronic intractable pain
• R52.2 – Other chronic pain
• R52.9 – Unspecified pain

Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction.

Carcinogenesis, mutagenesis: 3 % and 5 % of rats in the mid- and high- dose groups, respectively, of the 24-month carcinogenicity study were shown to have renal epithelial tumours (adenomas or carcinomas). However, no evidence of renal toxicity was observed in the low-dose group. An increased incidence of uterine adenocarcinomas was seen in the high-dose group of the rat carcinogenicity study. There were no similar renal findings in the mouse or dogs carcinogenicity studies.

Mutagenesis: Tolcapone was shown not to be genotoxic in a complete series of mutagenicity studies.

Toxicity to reproduction: Tolcapone, when administered alone, was shown to be neither teratogenic nor to have any relevant effects on fertility.

Adverse reactions possible when combined with:

• Benzodiazepines

• CNS depressants

• Antidepressants

• MAO inhibitors

No special requirements for disposal.